Process for producing 2-substituted cyclopentane-1, 3-diones



United States Patent 7 Claims. (Ci. 260-586) ABSTRACT ()F THE DHSCLOSURE2-alkyl cyclopentane-1,3-dione is prepared by (a) reactingcyclopent-4-ene-1,3-dione with a compound of the formula wherein R is Hor alkyl and R is alkyl with 1 to 4 carbon atoms. The resultant novelZ-alkoxyalkylidene cyclopent- 4-ene-1,3-dione is then (b) catalyticallyreduced with hydrogen to yield the desired compound.

The present invention relates to a process for producing Z-substitutedcyclopentane-l,3-diones. More concretely, the present invention relatesto a process for producing Z-Substituted cyclopentane-l,3-diones, whichcomprises allowing cyclopent-4-ene-1,3-dione to react with a lower alkylester of ortho-acid having the Formula (II):

C JR (II) wherein R is H or alkyl containing from 1 to 3 carbon atomsand R is alkyl containing from 1 to 4 carbon atoms, (e.g. methyl, ethyl,n-propyl, isopropyl and n-butyl), followed by subjecting the resultingZ-alkoxyalkylidenecyclopentl-ene-1,3-diones to a catalytic reduction.

Z-substituted cyclopentane-l,3-diones are useful as intermediates forsynthesizing steroids (cf. Chemistry and Industry, 1960, pages 10221023;Proceedings of Chemical Society, 196-3, page 139) and have been producedfrom the corresponding 1,3,4-triones by a series of reactions whereso-called Wolii-Kishner reduction or Clemmensen reduction is employed,

However, these known processes necessarily require the use of the2substituted cyclopentane-1,3,4-triones as the starting material andthis very requisite makes it difiicult to apply the known processes toindustrial production of the 2-substituted cyclopentane-1,3-diones. Oneof the main ditriculties is due to the property of the 1,3,4-trionesthat they have a high solubility in water but are hardly soluble inhydrophobic solvents. Consequently, an unreasonably long time andtroublesome procedures are required in order to purify the 1,3,4-trionesto a degree sufficiently high enough to be employed as the startingmaterial in the known processes. Another difficulty comes frominconveniences in operating the synthesis of the 1,3, 4-triones byseveral known synthetic courses to the 1,3,4- triones.

Furthermore, in the case of Wolff-Kishner reduction, there must be useda semicarbazide which is rather expensive for an industrial productionof the desired materials.

Therefore, in spite of the outstanding success in the elaborated totalsynthesis of steroids, one of the reasons why the total synthesis hasnot yet been successfully put into industrial production is attributableto the above- 3,381,035 Patented Apr. 30, 1968 mentioned drawbacks inthe known processes for the production of the 2-substitutedcyclopentane-1,3-diones.

In the course of study to overcome the foregoing difficulties and otherdisadvantages, the present inventors have unexpectedly found that alower alkyl ester of orthoacid is capable of reacting withcyclopent-4-ene-1,3-dione to introduce 2-alkoxyalkylidene group into the2-position of the latter, and furthermore, that when the resulting2-substituted cyclopent-4-ene-1,3-diones are brought into contact withabout three moles or a little more of hydrogen gas per molecule in thepresence of a known catalyst for catalytic reduction, thealkoxyalkylidene group at the 2-position and the 5:4-double bond areselectively reduced in one step without affecting the two oXo groups at1- and 3-positio11s, to produce the corresponding 2-alkylcyclopentane-l,3 diones in good yield.

In this kind of technical field, these phenomena can be regarded asquite unusual.

The process of this invention is based upon these phenomena, which areexcellently effective for the production of steroids on a commercialscale.

It is an object of the present invention to provide an eflfective andeconomical method for producing Z-substituted cyclopentane-1,3-diones.

Another object is to provide novel Z-alkoxyalkylidenecyclopentt-ene-l,3-diones by the process of the present invention.Namely, the present invention comprises reactingcyclopent-4-ene-1,3-diones with a lower alkyl ester of ortho-acid,whereby novel Z-alkoxyalkylidene cyclopent-4-ene-1,3-diones are formed,followed by subjecting the resulting product to a catalytic reduction.

The first step of the method of this invention is to reactcyclopent-4-ene-1,3-dione (Compound I) with a lower alkyl ester ofortho-acid (Compound II) to give 2-alkoxyalkylidenecyclopent-4-ene-1,3-diones (Compound 111).

The cyclopent-4-ene-1,3-dione is representable by Formula (1):

and may be prepared by known method, for example, by that described inOrganic Syntheses 42, 36, (1962).

The reaction between the cyclopent-4-ene-1,3-dione and lower alkyl esterof ortho-acid (II) is carried out with or without the use of an organicsolvent. Any compatible organic solvent, e. g. acetic anhydride,propionic anhydride, toluene, xylene or benzene, etc. may be used.

The reaction is accelerated by heating and also by the presence of anacid catalyst such as inorganic acids (e.g. sulfuric acid, phosphoricacid), sulfonic acids (e.g. methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid), so-called Lewis acids (e.g. boron trifluoride andzinc chloride), etc. t

It is usually preferred to carry out the reaction at a temperature ofabout 50-150 C. for about 10 hours.

When acetic anhydride or propionic anhydride is employed as organicsolvent, the corresponding ester is formed as a by-product, which may beeliminated from the reaction mixture by heating in order to displace theequilibrium towards acceleration of the reaction. Organic solvent usedmay be eliminated from the reaction system as azeotropic mixture for thesame purpose.

The resulting Z-alkoxyalkylidene cyclopent-4-ene-1,3- diones (III) arenovel, having a structure represented by the Formula (HI):

(III) l CH2 wherein R has the same meaning as defined in the Formula(V). Catalysts applicable to the reduction of the Compound (III) to thecorresponding Compound (IV) include, for example palladium, nickel,ruthenium or platinum catalysts. The reaction is usually carried out ina solvent. A desirable solvent can be selected from commonly usablecompatible organic solvents, and it may be exemplified as lower alcohols(e.g. methanol, ethanol, etc.), ketones (e.g. acetone, methyl ethylketone, cyclohexanone, etc.), ethers (e.g. tetrahydrofuran, dioxane,etc.) and the like.

As mentioned hereinbefore, by the use of the present invention theZ-stubstituted cyclopentane-l,3-diones can be prepared easily fromcyclopent-4-ene-1,3-dione as the starting material, and the process isremarkably useful for the industrial production of steroids.

For the purpose of giving those skilled in the art a better undersandingof the invention, the following illustrative examples of presentlypreferred embodiments are given.

In these examples, parts are by weight unless otherwise specified, andparts by weight bear the same relation to parts by volume as do grams tomilliliters.

EXAMPLE 1 To a solution of 3 parts of cyclopent-4-ene-l,3-dione in 7.2parts of acetic anhydride are added 5.4 parts of ethyl orthoformate and0.5 part of anhydrous zinc chloride. The mixture is agitated at 7080 C.for 6 hours While removing ethyl acetate from the reaction system byevaporation, and then filtered to remove zinc chloride. The filtrate isconcentrated and cooled to give crystals, which are recrystallized fromether to give 2-ethoxy methylidene cyclopent-4-ene-l,3-dione asyellowish needles melting at 80-815 C. Yield: 2.5 parts.

Elementary analysis.Calculated for C H O 63.15%; H, 5.30%. Found: C,63.77%; H, 5.21%.

Ultraviolet absorption:

x533, 253111,. (e=l7,000); 221.5111 (6=15,700). Nuclear magneticresonance (in tetrachloromethane) 1' 3.50 (2Ea-CHg-) /C=O H To asolution of 0.4 part of thus obtained 2-ethoxymethylidenecyclopent-4-ene-l,3-dione in 50 parts by volume of ethyl alcohol isadded 0.3 part of palladium-carbon as a catalyst. The mixture is shakenin a stream of hydrogen gas. After 190 parts by volume of hydrogen gas(15 C., 1 atm.) are absorbed, the mixture is filtered to remove thecatalyst. The filtrate is concentrated to leave 0.28 part of crystals,which are recrystallized from water to obtain 2-methylcyclopentane-l,3-dione as slightly yellowish needles melting at 205-2l0C.

Use of 0.3 part of 5% Raney-nickel as catalyst in place of 0.3 part of5% palladium-carbon gives a result similar to the above.

EXAMPLE 2 To a solution of 2 parts of cyclopent-4-ene-1,3-dione in 9.5parts of acetic anhydride are added 7.4 parts of ethyl orthopropionateand 0.8 part of anhydrous zinc chloride. The mixture is agitated at 90C. for 4 hours while removing ethyl acetate from the reaction system byevaporation, and then filtered to remove zinc chloride. The filtrate isconcentrated to give a black oily residue, which is subjected tochromatography by the use of a column packed with silica gel, and thecolumn is then eluted with benzene to obtain 1.5 parts of 2-ethoxypropylideue cyclopent-4-ene-1,3-dione as yellowish substance.

kEtOH max.

Ultraviolet absorption:

To a solution of 1 part of thus-obtained Z-ethoxypropylidenecyclopent-4-ene-1,3-dione in 70 parts by volume of ethyl alcohol isadded 0.1 part of 5% palladium-carbon as catalyst, and the mixture isshaken in a hydrogen stream. After 390 parts by volume of hydrogen (20C., 1 atm.) are absorbed, the mixture is filtered to remove thecatalyst. The filtrate is concentrated to leave crystals, which arerecrystallized from a mixture of Water and ethyl alcohol (8:2) to obtain0.7 part of 2-propyl-cyclopentane- 1,3-dione as colorless scalycrystals.

Elementary analysis.Calculated for C H O 68.54%; H, 8.63%. Found: C,68.89%; H, 8.53%.

Ultraviolet absorption: A212, 250.5 m (6 16, 240) Infrared absorption:mi 3,0001,700 cmf (broad); 1,550 GEL-1.

Use of 0.1 part of 5% Raney-nickel as catalyst in place of 0.1 part of5% palladium-carbon gives a similar result as above.

What is claimed is:

1. A compound of the formula:

wherein R is H or alkyl containing from 1 to 3 carbon atoms and R isalkyl containing from 1 to 4 carbon atoms.

2. A compound of the formula:

3. A compound of the formula:

H(IJO c2115 4. A process for the production of 2-alkyl cyclopentane-1,3-dione of the formula:

wherein R is H or alkyl with from 1 to 3 carbon atoms, which comprisesbringing Z-alkoxyalkylidene cyclopent-4- ene-1,3-dione of the formula:

wherein R is alkyl containing from 1 to 4 carbon atoms and R has thesame meaning as defined above, into contact with hydrogen in thepresence of a catalyst selected from the group consisting of palladium,nickel, ruthenium and platinum catalysts.

5. A process for producing a compound of the formula wherein R is H oralkyl containing from 1 to 3 carbon atoms, which comprises (a) reactingcyclopent-4-ene-1,3-dione with a lower alkyl ester of orthoacid of theformula:

OR RC )0 R 6R" wherein R is alkyl containing from 1 to 4 carbon atomsand R has the same meaning as defined above, at a temperature of aboutto C. to produce a compound of the formula:

(b) bringing the resultant compound into contact with hydrogen in thepresence of a catalyst selected from the group consisting of palladium,nickel, ruthenium and platinum catalysts.

6. A process according to claim 4 wherein the reduction catalyst isRaney nickel.

7. A process according to claim 4 wherein the reduction catalyst ispalladium-carbon.

and

